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Molecular Mechanisms of Dendrite Stability

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Molecular Mechanisms of Dendrite Stability REVIEWS Molecular mechanisms of dendrite stability Anthony J. Koleske Abstract | In the developing brain, dendrite branches and dendritic spines form and turn over dynamically. By contrast, most dendrite arbors and dendritic spines in the adult brain are stable for months, years and possibly even decades. Emerging evidence reveals that dendritic spine and dendrite arbor stability have crucial roles in the correct functioning of the adult brain and that loss of stability is associated with psychiatric disorders and neurodegenerative diseases. Recent findings have provided insights into the molecular mechanisms that underlie long-term dendrite stabilization, how these mechanisms differ from those used to mediate structural plasticity and how they are disrupted in disease. The proper formation and long-term maintenance of as it affords mature neurons the ability to fine-tune spine- neuronal connectivity is crucial for correct function- based synaptic connections, while retaining overall long- ing of the brain. The size and shape of a neuron’s den- term dendrite arbor field integrity and integration within drite arbor determine the number and distribution of networks. Furthermore, cytoskeletal stability is crucial receptive synaptic contacts it can make with afferents. for maintaining long-lasting synaptic changes such as During development, dendrites undergo continual long-term potentiation (LTP). Examining the distinct dynamic changes in shape to facilitate proper wiring, mechanisms that mediate spine and dendrite stability is synapse formation and establishment of neural circuits. the major focus of this Review. Dendrite arbors are highly dynamic during develop- By adulthood, the dynamic behaviour of spines is ment, extending and retracting branches as they mature, greatly reduced. Transcranial two-photon imaging indi- and only a subset of nascent dendrite branches become cates that a large fraction of dendritic spines in the adult stabilized1–4 (FIG. 1). During this early wiring period, rodent cortex are stable for extended time periods of synapse and dendrite arbor stabilization are intimately several months and possibly years15–18,27 (FIG. 1). Together, connected. For example, synapse formation on a nascent these findings suggest a scenario in which most dendritic dendrite branch promotes its stabilization, whereas the spines and dendrite arbors become stabilized for long loss or reduction of synaptic inputs destabilizes target periods of an organism’s lifetime, perhaps even for dendrites4–13. decades in humans. The structural plasticity of dendrites decreases Losses of dendritic spine and dendrite arbor stability greatly as circuits mature (FIG. 1). Most dendrite branches in humans are major contributing factors to the pathol- become stabilized first while individual dendritic spines ogy of psychiatric illnesses such as schizophrenia and continue to form, change shape and turn over as circuits major depressive disorder (MDD), neurodegenerative refine14–18. During this period, the formation and prun- diseases, such as Alzheimer’s disease, and damage from ing of spines is particularly sensitive to experience and stroke. Importantly, different patterns of dendritic spine Departments of Molecular activity patterns16,18–20. This is followed by a period of and dendrite branch loss are observed in different psy- Biophysics and Biochemistry and Neurobiology, extensive synapse and dendritic spine pruning, which chiatric and neurodegenerative disorders (reviewed in Yale University, can can last throughout adolescence and early adulthood REF. 28), suggesting that spine and branch stabilization 333 Cedar Street SHMC‑E31, in some human brain regions17,20–26. In stark contrast to mechanisms are differentially disrupted in different New Haven, Connecticut early development, in which stabilization of dendrite disease pathologies. The altered synaptic connectivity 06520–8024, USA. branches depends critically on synapse formation, den- resulting from dendrite arbor and dendritic spine desta- e‑mail: anthony.koleske@ yale.edu dritic spine and dendrite branch stability become mecha- bilization is thought to contribute to the impaired per- doi:10.1038/nrn3486 nistically uncoupled during this late refinement period. ception, cognition, memory, mood and decision-making Published online 10 July 2013 Such uncoupling is crucial for long-term circuit stability, that characterize these pathological conditions. 536 | AUGUST 2013 | VOLUME 14 www.nature.com/reviews/neuro © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS a b c E15–P21 P21–P60 P60 onwards Few spines Spines dynamic Spines dynamic Spines (mostly) Axon stabilize Branches dynamic Branches stabilize Branches stabilize Figure 1 | Dendrite branch and dendritic spine dynamics change during development. Naturea | During Reviews early |development Neuroscience in mice (embryonic day 15 (E15) to postnatal day 21 (P21)), dendritic branches are highly dynamic, extending new branches (green) and retracting some existing branches (red). Failure to form productive synaptic contacts (inset, red dendrite segment) results in fewer spines and dendrite branch retraction; more stable branches (inset, green dendrite segment) contain a mix of stable spines, new spines and destabilizing spines. b | As animals enter and transit adolescence (P21–P60), some dendrite branches stabilize, while a fraction of dendritic spines remain dynamic, with a net loss of spines. c | As animals enter adulthood, dendritic spine dynamics slow and most of the spines remain stable. A growing number of recent studies have begun to Direct measurements using sophisticated live micros- dissect the mechanisms that mediate long-term den- copy techniques reveal that actin exists in distinct dritic spine and dendrite branch stability. Here, I pro- pools that differ in their movement and stability vide an up‑to‑date review of the molecules (TABLE 1) and within the spine36,43,44. Photoactivation studies indicate cellular and molecular mechanisms that differentially that actin at the spine tip and periphery, also known as regulate dendritic spine versus dendrite branch stabil- the spinoskeleton ‘shell’, is dynamic, cycling between ity and highlight how these mechanisms are targeted by monomeric globular and polymeric (filamentous) pathology. forms that turn over with half-lives of tens of seconds. By contrast, actin in the centre and base of the spine, Determinants of dendrite and spine stability also known as the spinoskeleton ‘core’, turns over in Dendritic spines are supported by an F‑actin framework. At tens of minutes43. Consistent with this model, when most excitatory synapses, presynaptic boutons synapse onto single photoactivated actin molecules were tracked in small dendritic spines that emerge from the dendritic shaft. spines, half remained largely stationary, as would be Spines have diverse shapes, including thin, short and stubby, expected of actin associated with a more stable actin and mushroom-shaped, with a club-like head and thinner core, whereas one-third underwent slow retrograde neck15,29–32. Dendritic spines are enriched in filamentous (F) movement, which is consistent with a more dynamic actin, which provides the spine shape, organizes the postsyn- pool of actin associated with the shell44. It has recently aptic signalling machinery, drives changes in spine structure been noted that distinct actin-binding proteins (ABPs) and maintains spine stability33–37. The spine cytoskeleton localize to discrete regions within the spinoskeleton38. (referred to here as the ‘spinoskeleton’)38 is composed of a For example, cortactin, which both stimulates actin mix of linear and branched actin networks, which extend polymerization and stabilizes branched actin net- from the base of the spine to the postsynaptic density works, localizes to the spinoskeleton core45, whereas (PSD)31,39. This actin network fills the spine — it is closely cofilin, an F‑actin-severing protein that is associated apposed to the spine membrane, and it retains this associa- with dynamic F‑actin turnover, localizes to the shell46 tion during activity-driven remodelling of spine structure31 (FIG. 2). Together, these studies suggest that the periph- (FIG. 2). Changes in the amount and structure of F‑actin also ery of spine structure — near the outer membrane mediate long-lasting alterations in spine size and synaptic — is likely to be capable of greater morphological efficacy. For example, repetitive firing of synapses, such as change, whereas the central core remains more sta- that occurring during high-frequency synaptic stimulation ble. This is consistent with the observation that spines to induce LTP, promotes actin polymerization within the can be highly motile and could reflect a need, during spine, causing the spine to enlarge40,41. Conversely, treat- synaptogenesis, to keep the overall position of new ment that weakens synaptic efficacy, such as low-frequency spines constant while the more dynamic outer portion stimulation that results in long-term depression, causes actin searches for suitable synaptic contacts or adjusts in size loss and dendritic spine shrinkage40,42. in response to new activity patterns. NATURE REVIEWS | NEUROSCIENCE VOLUME 14 | AUGUST 2013 | 537 © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Table 1 | Molecules influencing dendritic spine and dendrite arbor stability actin filaments and microtubules that make up their structures turn over in matters of minutes to hours; this Key molecules Refs is the
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